TREM-1 and Its Implications to Cancer

Description

AbstractA connection between inflammation and cancer has been long suspected. New insights into the molecular linkbetween inflammation and tumorigenesis would be beneficial for the development of novel strategies thattarget inflammation for use in both cancer prevention and therapy. New molecules that control inflammatoryresponses would provide a novel therapeutic possibility to prevent and reduce the incidence of cancer.Triggering receptor expressed on myeloid cells 1 (TREM-1) is one of these potential candidates. TREM-1 playsa crucial role in enhancing inflammatory responses through amplifying the expression of proinflammatorycytokines and chemokines. TREM-1 has limited expression; it is expressed on neutrophils and can be inducedon monocytes and macrophages. We have determined that inhibition of TREM-1 affects livertumorigenesis. Our preliminary data suggest that deletion of the Trem1 gene provides resistance todevelopment of chemical-induced hepatocellular carcinoma in a murine model. We have identified apreviously unknown TREM-1 ligand, HMGB1 (High Mobility Group Box1) that is released by necrotichepatocytes and is involved in activation of Kupffer cells, which creates an inflammatory environmentthat, in turn, causes hepatocyte compensatory proliferation, leading to carcinogenesis. Our data revealan essential contribution of TREM-1 on Kupffer cells in regulating or co-regulating the inflammatory responseto inducers of chronic inflammation in damaged tissues. Thus, we have identified novel inductionmechanisms of chronic inflammation leading to carcinogenesis. This application addresses the analysis of a new function of TREM-1 in tumorigenesis. The goal of thisresearch is to determine the impact and mechanisms of TREM-1 regulation of liver tumorigenesis and todesign better strategies for potent anti-cancer prevention and development of new therapeutic approaches thattarget immune and non-immune components in liver tumors. The central hypothesis of this application,based on our strong preliminary data involving TREM-1-deficient mice, is that inhibition of TREM-1modulates inflammatory responses, which results in diminished development of hepatocellularcarcinoma. This knowledge will be crucial in designing the most potent treatment of inflammation-associated cancer. Our hypothesis is reflected in our study of the impact and mechanisms of TREM-1regulation in tumorigenesis, the potential of inhibitors of TREM-1 to suppress the development of chemical- oroncogene-induced liver tumorigenesis (Specific Aim 1), and the function of TREM-1 in liver cancer cells(Specific Aim 2). Data obtained from these studies will reveal the role of TREM-1 in modulation oftumorigenesis and will aid in development of novel strategies that can be translated into the clinic forprevention and therapy of liver cancer. Additionally, this research may benefit patients with a variety ofinflammatory diseases, including allergy and autoimmune diseases.